The goal of this research project is to assess the role of oxidative stress as a factor in noise-induced hearing loss (NIHL), the primary cause of hearing loss in the industrialized world. Noise induced metabolic activity of inner ear as well as direct mechanical trauma may result in the formation of reactive oxygen species (ROS). We propose a model in which ROS represent a major causal factor in NIHL leading to downstream cascades that result in cell death. The model proposes that noise induces the formation of ROS, and that ROS and their byproducts directly cause pathology of the inner ear tissues, as well as indirectly cause a reduction in inner ear blood flow that exacerbates tissue damage. The model also proposes interventions that can block the formation and direct effects of ROS (antioxidants) or their downstream cascades (neurotrophic factors, NTF), and thus may protect the inner ear from noise damage. The studies proposed will test the hypotheses that: 1) noise induces ROS and inner ear pathology, and that antioxidant treatment prior to noise exposure will reduce ROS (lipid peroxidation) and NAIL (measured electrophysiologically and by sensory cell damage in guinea pigs); 2) cochlear blood flow is reduced by isoprostanes, products of lipid peroxidation, further contributing to NIHL; 3) NTF will significantly reduce NIHL while minimally reducing ROS; 3) post noise-exposure treatment will afford reduced, but significant, protection (compared to pretreatment). These studies are geared towards identifying the specific ROS formed and the time course of their formation. They will allow us to specifically assess the relative effectiveness of antioxidants and NTFs to reduce ROS-induced cell destruction. These studies will provide a critical test of this model of NIHL and may lead to interventions that are effective in preventing NIHL.